Alzheimer Disease (AD) is the most common age-related neurodegenerative disorder associated with progressive loss of cognitive function, which currently afflicts up to 5 million people in the US alone. Characteristic neuropathological changes seen in AD brain include synaptic and neuronal loss, neurofibrillary tangles (NFTs), extracellular senile plaques composed of amyloid (A) protein deposits and evidence of inflammatory events. The relative contributions of these pathological markers to the cognitive dysfunction in AD remains controversial, but results from studies in both AD patients and transgenic mouse models of AD, make it likely that multiple, overlapping processes contribute to neuronal degeneration and cognitive loss. In human studies, clinically significant cognitive decline occurs at the stage of the disease in which fibrillar A plaques and NFT are present; however, it is becoming increasingly evident that the presence of fibrillar plaques is not sufficient for clinical diagnosis of AD, and, thus it is now acknowledged by most in the field that other factors are also critical in loss of cognition. Our recent studies demonstrated that treatment with PMX205, a small molecular weight cyclic hexapeptide C5a receptor (CD88) antagonist, significantly reduced neuropathology and improved performance in a passive avoidance task for contextual memory in transgenic mouse models of AD relative to untreated transgenic animals. The results support the hypothesis that the inhibition of C5a-induced inflammation reduces amyloid and tangle accumulation, reduces synapse loss, and contributes to the prevention or rescue of a deficit in a hippocampal dependent memory task. The fact that these effects occur when the drug was delivered during the period of time that plaques are normally accumulating in these models, suggests that inhibition of complement-induced inflammation might substantially slow the snowballing cascade of cognitive decline in AD, even after the initial stages of impairment are diagnosed. This therapeutic target is distinct from other heavily investigated approaches for AD therapies. Thus far, PMX205 is specific for CD88/C5aR in contrast to other proposed inhibitors that may affect a target (s) that can have detrimental off target effects such as kinase inhibitors, caspase inhibitors, and less specific immune suppressors. The specific aims of this proposal are to define whether the drug provides its beneficial action by acting in the periphery or within the brain itself, determine at what time the drug gains access to the brain and whether the drug is effective for extended periods of time, assess whether the drug can reverse cognitive loss in an animal model of AD or merely stop/slow progression of the disease, and finally to delineate the cell types (neurons or glia) involved and define the molecular mechanism of action of the drug in slowing the progression of neuropathology. That is, the central goal of this renewal project is to investigate the potential of an antagonist to a component activation fragment receptor (CD88) as a therapeutic target for treatment of Alzheimer Disease (AD) and to optimize a therapeutic strategy directed at blocking the proinflammatory signaling mediated by complement activation. PUBLIC HEALTH RELEVANCE: In the U.S. alone, it is estimated that 5 million people are afflicted with Alzheimer's Disease, the most common form of age-related dementia. The cost of Alzheimer's Disease is estimated 148 billion dollars annually in the US. Studies in the previous research period discovered promising effects of a cyclic hexapeptide antagonist of a complement system activation fragment in reducing pathology and avoiding cognitive loss in 2 mouse models. Thus, the current proposal will focus on further preclinical evaluation of this specific reagent, development and evaluation of new compounds that target this specific receptor, and validation of the fundamental mechanism(s) by which the beneficial effect occurs.